Diabetes comprises two distinct diseases, type 1 (or insulin-dependent diabetes) and type 2 (insulin-independent diabetes), both of which involve the malfunction of glucose homeostasis. Type 2 diabetes affects more than 350 million people in the world and the number is rising rapidly. Complications of diabetes include severe cardiovascular problems, kidney failure, peripheral neuropathy, blindness and even loss of limbs and death in the later stages of the disease. Type 2 diabetes is characterized by insulin resistance in skeletal muscle and adipose tissue (fat), and at present there is no definitive treatment. Most treatments used today are focused on treating dysfunctional insulin signaling or inhibiting glucose output from the liver and many of those treatments have several drawbacks and side effects. There is thus a great interest in identifying novel insulin-independent ways to treat type 2 diabetes.
The major type 2 diabetes symptom is loss of response to insulin in peripheral tissues, meaning that adipose tissue and skeletal muscles are unable to increase glucose uptake upon insulin stimulation. One possible approach is to find insulin-independent ways to stimulate glucose uptake in peripheral tissues such as skeletal muscle, the major glucose clearing organ.
Adrenergic receptors are expressed in several tissues, such as lungs, heart, blood vessels and liver. It has been reported that beta-adrenergic receptor agonists can increase glucose uptake in brown adipocytes and skeletal muscle cells in vitro through an insulin-independent way (Liu, Cawthorne & Stock 1996, Ngala et al. 2008, Ngala et al. 2009). However, most effects of beta-adrenergic receptors have been attributed to the cAMP increase and most or all of the beta-adrenergic effect on glucose uptake has been attributed to cAMP. The increase of cAMP has many effects in different tissues. For example, it increases heart rate, regulates blood flow, airflow in lungs and increases release of glucose from the liver, which all can be detrimental or be considered unwanted side effects if a beta agonists should be considered as a diabetes treatment. Adverse effects of beta-adrenergic receptor agonist and cAMP elevation are for example tachycardia, palpitation, tremor, sweats, agitation and increased glucose levels in the blood (glucose output from the liver). All these effects can be attributed to the beta-adrenergic stimulated elevation of cAMP in various tissues.
Also functions associated with glucose homeostasis may be affected: secretion of both glucagon and insulin been suggested to be increased by β-adrenergic signaling (Lacey et al. 1991, Ahren et al. 1981), as well hepatic gluconeogenesis and glycolysis (Exton 1987, Vardanega-Peicher et al. 2000) which increases glucose output from the liver.
It appears therefore that using standard adrenergic agonists to treat diabetes is not a possible approach.
Facilitative glucose transporters (GLUT) mediate glucose uptake into most cells. GLUT are transporter proteins that mediate transport of glucose and/or fructose over the plasma membrane down the concentration gradient. There are fourteen known members of the GLUT family, named GLUT1-14, divided into three classes (Class I, Class II and Class III) dependent on their substrate specificity and tissue expression. GLUT1 and GLUT4 are the most intensively studied iso forms and, together with GLUT2 and GLUT3, belong to Class I which mainly transports glucose (in contrast to Class II that also transports fructose). GLUT1 is ubiquitously expressed and is responsible for basal glucose transport. GLUT4 is only expressed in peripheral tissues such as skeletal muscle, cardiac muscle and adipose tissues. GLUT4 has also been reported to be expressed in e.g. brain, kidney, and liver. GLUT4 is the major isoform involved in insulin stimulated glucose uptake. To treat a condition involving a dysregulation of glucose homeostasis or glucose uptake in a mammal, it is of paramount importance to activate certain GLUTs. For example for diseases such as type 2 diabetes it is vital to activate GLUT4 translocation to the plasma membrane and thus glucose uptake.
Regulation of GLUT1 translocation or intrinsic activity has been suggested to occur in several tissues including erythrocytes depending on ATP-levels (Hebert, Carruthers 1986). It has also been indicated in HEK-cells (Palmada et al. 2006), 3T3-L1 (Harrison, Buxton & Czech 1991, Harrison et al. 1992) and clone-9 cells (Barnes et al. 2002).
Impaired GLUT translocation, of in particular GLUT8, has been reported as involved in both male and female infertility (Gawlik et al. 2008, Carayannopoulos et al. 2000).
The mechanism whereby insulin signaling increases glucose uptake is mainly via GLUT4-translocation from intracellular storage to the plasma membrane (Rodnick et al. 1992). After longer insulin stimulation also GLUT1-content is increased due to increased transcription (Taha et al. 1995).
Glucose uptake in type 2 diabetes is associated with defects in PI3K activity, insulin receptor tyrosine, IRS and Akt phosphorylation, resulting in impairment of GLUT4 translocation to the plasma membrane.
Impaired GLUT translocation also plays a role in muscle wasting. Furthermore, GLUT translocation plays a role in feeding behavior. Mice lacking GLUT4 develop problems with lipid and glucose homeostasis leading to changes in feeding behavior.
Decreased concentrations of GLUT1 and GLUT3 have also been shown in the brains of patients with Alzheimer's disease (Simpson et al. 2008).
Also in a review article of Shah K, et al. (Shah, Desilva & Abbruscato 2012) the role of glucose transporters in brain disease, diabetes and Alzheimer's disease is discussed.